Petersen, A. J. | bioRxiv Science

bioRxiv2025

The β-amyloid oligomer Aβ*56 is associated with Alzheimer's dementia independently of amyloid pathology

The amyloid cascade hypothesis posits that {beta}-amyloid (A{beta}) oligomers (A{beta}o) play a key role in the pathogenesis of Alzheimers disease (AD). A{beta}o are believed to contribute to dementia in AD, and more than a dozen have been identified. While some oligomers are associated with amyloid plaques, others--such as A{beta}*56--are not. It remains unclear whether these plaque-independent oligomers contribute to dementia. A{beta}*56 is a non-fibrillar, sodium dodecyl sulfate-stable, brain-derived type of A{beta}o that impairs memory in mice. We recently confirmed and extended the characterization of A{beta}*56 in AD mouse models and identified two variants, namely A{beta}(40)*56 and A{beta}(42)*56 containing canonical A{beta}(1-40) and A{beta}(1-42), respectively. To examine the role of A{beta}*56 in dementia, we measured A{beta}*56 in elderly individuals--selected for equivalent levels of amyloid plaques--with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia. Using immunoprecipitation (IP), western blotting (WB), size exclusion chromatography, and conformation-sensitive antibodies, we confirmed the presence of A{beta}(40)*56 and A{beta}(42)*56 in human brains. Using IP/WB coupled with densitometry-based semi-quantitative analysis, we found that levels of both A{beta}*56 variants were elevated in AD dementia compared to NCI and MCI and correlated inversely with various measures of memory and cognition. Furthermore, mediation analyses showed that these associations were mediated by phosphorylated tau at serine 202 and threonine 205 (ptau 202/205)-containing neurofibrillary tangles. These findings support an association between A{beta}*56 and AD dementia independently of amyloid pathology. The results are significant because they suggest that targeting A{beta}*56 in patients could provide additional cognitive benefits beyond those achieved by current anti-A{beta} therapies that focus on removing amyloid plaques.

biochemistry↗

bioRxiv2021

Chemically Induced Senescence in Human Stem Cell-Derived Neurons Promotes Phenotypic Presentation of Neurodegeneration

Modeling age-related neurodegenerative disorders with human stem cells is difficult due to the embryonic nature of stem cell derived neurons. We developed a chemical cocktail to induce senescence of iPSC-derived neurons to address this challenge. We first screened small molecules that induce embryonic fibroblasts to exhibit features characteristic of aged fibroblasts. We then optimized a cocktail of small molecules that induced senescence in fibroblasts and cortical neurons without causing DNA damage. The utility of the "senescence cocktail" was validated in motor neurons derived from ALS patient iPSCs which exhibited protein aggregation and axonal degeneration substantially earlier than those without cocktail treatment. Our "senescence cocktail" will likely enhance the manifestation of disease-related phenotypes in neurons derived from iPSCs, enabling the generation of reliable drug discovery platforms.

neuroscience↗